Synaptic plasticity is thought to shape the connectivity of neural circuits, and to maintain the stability of neural circuits for optimal information processing. Connectivity is shaped, at least in part, by Hebbian-type plasticity, which adjusts the strength of a subset of synapses in a circuit in an input-specific fashion. In contrast, network stability is maintained via homeostatic synaptic plasticity, which modifies all synapses of a neuron concurrently in a multiplicative fashion (referred to as synaptic scaling). We recently demonstrated that all-trans retinoic acid (RA) directly acts on synapses to increase synaptic strength by inducing the synaptic insertion of GluR1-type AMPA receptors, and that the action of RA is essential for at least some forms of homeostatic plasticity. Moreover, we showed that RA may act by binding to dendritically localized RAR1 receptors in synapses, and that RA-signaling may intersect with Hebbian-type synaptic plasticity. These findings lead us to the overall hypothesis that RA constitutes a novel diffusible messenger in synapses that serves to regulate synaptic strength in response to external stimuli by altering postsynaptic GluR1 receptor levels. To test this overall hypothesis, we propose three specific aims that focus on key questions emerging from this hypothesis, and will primarily employ physiological measurements in hippocampal neurons. Aim 1 will examine the role of RA in various forms of homeostatic plasticity and short-term synaptic plasticity to explore the generality of its action. Results from this aim will define the physiological framework under which RA operates. Aim 2 will test the role of RA-binding to RAR1 in regulating hippocampal synaptic strength using conditional deletion of RAR1 in vitro in cultured neurons and slices, and employ rescue experiments to explore the relative contribution of various RAR1 protein domains to its synaptic function. Aim 3 will conditionally delete RAR1 in mice in vivo (as opposed to culture preparations) to investigate the functional interplay between RA-mediated synaptic scaling and Hebbian plasticity in vivo. Together, these experiments will thus utilize innovative approaches to explore the unexpected role of RA and RAR1 in hippocampal synaptic transmission, and provide initial insights into their mechanism of action. The significance of these experiments not only rests on their implications for understanding of synaptic transmission, but also on their potential relevance for retinoids-related neurological disorders such as depression and memory loses. PUBLIC HEALTH RELEVANCE: RA signaling has been implicated in learning and memory as well as mood disorders. However, we are at the beginning of our understanding of the molecular mechanisms involved in RA signaling and synaptic function. Work proposed here will increase our understanding of the fundamental mechanisms involved in RA-mediated synaptic plasticity, which will broaden our view of brain function and may help in developing novel therapies for neurological disorders.